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      Treatment of chronic active antibody-mediated rejection in renal transplant recipients – a single center retrospective study

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          Abstract

          Background

          Chronic active antibody-mediated rejection is a major etiology of graft loss in renal transplant recipients. However, there is no consensus on the optimal treatment strategies.

          Methods

          Computerized records from Taichung Veterans General Hospital were collected to identify renal transplant biopsies performed in the past 7 years with a diagnosis of chronic active antibody-mediated rejection. The patients were divided into two groups according to treatment strategy: Group 1 received aggressive treatment (double filtration plasmapheresis and one of the followings: rituximab, intravenous immunoglobulin, antithymogycte globulin, bortezomib, or methylprednisolone pulse therapy); and group 2 received supportive treatment.

          Results

          From February 2009 to December 2017, a total of 82 patients with biopsy-proven chronic antibody mediated rejection were identified. Kaplan-Meier analysis of death-censored graft survival showed a worse survival in group 2 ( P = 0.015 by log-rank test). Adverse event-free survival was lower in group 1, whereas patient survival was not significantly different. Proteinuria and supportive treatment were independent risk factors for graft loss in multivariate analysis.

          Conclusions

          Aggressive treatment was associated with better graft outcome. However, higher incidence of adverse events merit personalized treatment, especially for those with higher risk of infection. Appropriate prophylactic antibiotics are recommended for patients undergoing aggressive treatment.

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          Assessment of Tocilizumab (Anti-Interleukin-6 Receptor Monoclonal) as a Potential Treatment for Chronic Antibody-Mediated Rejection and Transplant Glomerulopathy in HLA-Sensitized Renal Allograft Recipients.

          A Loupy, M. Haas, J Kahwaji … (2017)
          Extending the functional integrity of renal allografts is the primary goal of transplant medicine. The development of donor-specific antibodies (DSAs) posttransplantation leads to chronic active antibody-mediated rejection (cAMR) and transplant glomerulopathy (TG), resulting in the majority of graft losses that occur in the United States. This reduces the quality and length of life for patients and increases cost. There are no approved treatments for cAMR. Evidence suggests the proinflammatory cytokine interleukin 6 (IL-6) may play an important role in DSA generation and cAMR. We identified 36 renal transplant patients with cAMR plus DSAs and TG who failed standard of care treatment with IVIg plus rituximab with or without plasma exchange. Patients were offered rescue therapy with the anti-IL-6 receptor monoclonal tocilizumab with monthly infusions and monitored for DSAs and long-term outcomes. Tocilizumab-treated patients demonstrated graft survival and patient survival rates of 80% and 91% at 6 years, respectively. Significant reductions in DSAs and stabilization of renal function were seen at 2 years. No significant adverse events or severe adverse events were seen. Tocilizumab provides good long-term outcomes for patients with cAMR and TG, especially compared with historical published treatments. Inhibition of the IL-6-IL-6 receptor pathway may represent a novel approach to stabilize allograft function and extend patient lives.
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            A Randomized Trial of Bortezomib in Late Antibody-Mediated Kidney Transplant Rejection

            Farsad Eskandary, Heinz Regele, Lukas Baumann … (2018)
            Late antibody-mediated rejection (ABMR) is a leading cause of kidney allograft failure. Uncontrolled studies have suggested efficacy of the proteasome inhibitor bortezomib, but no systematic trial has been undertaken to support its use in ABMR. In this randomized, placebo-controlled trial (the Bortezomib in Late Antibody-Mediated Kidney Transplant Rejection [BORTEJECT] Trial), we investigated whether two cycles of bortezomib (each cycle: 1.3 mg/m2 intravenously on days 1, 4, 8, and 11) prevent GFR decline by halting the progression of late donor-specific antibody (DSA)-positive ABMR. Forty-four DSA-positive kidney transplant recipients with characteristic ABMR morphology (median time after transplant, 5.0 years; pretransplant DSA documented in 19 recipients), who were identified on cross-sectional screening of 741 patients, were randomly assigned to receive bortezomib (n=21) or placebo (n=23). The 0.5-ml/min per 1.73 m2 per year (95% confidence interval, -4.8 to 5.8) difference detected between bortezomib and placebo in eGFR slope (primary end point) was not significant (P=0.86). We detected no significant differences between bortezomib- and placebo-treated groups in median measured GFR at 24 months (33 versus 42 ml/min per 1.73 m2; P=0.31), 2-year graft survival (81% versus 96%; P=0.12), urinary protein concentration, DSA levels, or morphologic or molecular rejection phenotypes in 24-month follow-up biopsy specimens. Bortezomib, however, associated with gastrointestinal and hematologic toxicity. In conclusion, our trial failed to show that bortezomib prevents GFR loss, improves histologic or molecular disease features, or reduces DSA, despite significant toxicity. Our results reinforce the need for systematic trials to dissect the efficiency and safety of new treatments for late ABMR.
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              Treatment of chronic antibody mediated rejection with intravenous immunoglobulins and rituximab: A multicenter, prospective, randomized, double-blind clinical trial.

              Francesc Moreso, Marta Crespo, Juan Ruiz … (2018)
              There are no approved treatments for chronic antibody mediated rejection (ABMR). We conducted a multicenter, prospective, randomized, placebo-controlled, double-blind clinical trial to evaluate efficacy and safety of intravenous immunoglobulins (IVIG) combined with rituximab (RTX) (EudraCT 2010-023746-67). Patients with transplant glomerulopathy and anti-HLA donor-specific antibodies (DSA) were eligible. Patients with estimated glomerular filtration rate (eGFR) <20 mL/min per 1.73m2 and/or severe interstitial fibrosis/tubular atrophy were excluded. Patients were randomized to receive IVIG (4 doses of 0.5 g/kg) and RTX (375 mg/m2 ) or a wrapped isovolumetric saline infusion. Primary efficacy variable was the decline of eGFR at one year. Secondary efficacy variables included evolution of proteinuria, renal lesions, and DSA at 1 year. The planned sample size was 25 patients per group. During 2012-2015, 25 patients were randomized (13 to the treatment and 12 to the placebo group). The planned patient enrollment was not achieved because of budgetary constraints and slow patient recruitment. There were no differences between the treatment and placebo groups in eGFR decline (-4.2 ± 14.4 vs. -6.6 ± 12.0 mL/min per 1.73 m2 , P-value = .475), increase of proteinuria (+0.9 ± 2.1 vs. +0.9 ± 2.1 g/day, P-value = .378), Banff scores at one year and MFI of the immunodominant DSA. Safety was similar between groups. These data suggest that the combination of IVIG and RTX is not useful in patients displaying transplant glomerulopathy and DSA.
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                Author and article information

                Contributors
                Kuo-Hsiung Shu: khshudr@gmail.com
                Journal
                Journal ID (nlm-ta): BMC Nephrol
                Journal ID (iso-abbrev): BMC Nephrol
                Title: BMC Nephrology
                Publisher: BioMed Central (London )
                ISSN (Electronic): 1471-2369
                Publication date (Electronic): 6 January 2020
                Publication date PMC-release: 6 January 2020
                Publication date Collection: 2020
                Volume: 21
                Electronic Location Identifier: 6
                Affiliations
                [1 ]ISNI 0000 0004 0573 0731, GRID grid.410764.0, Division of Nephrology, Department of Internal Medicine, , Taichung Veterans General Hospital, ; Taichung, Taiwan
                [2 ]ISNI 0000 0004 0573 0731, GRID grid.410764.0, Department of Pathology and Laboratory Medicine, , Taichung Veterans General Hospital, ; Taichung, Taiwan
                [3 ]ISNI 0000 0004 0573 0731, GRID grid.410764.0, Division of Urology, Department of Surgery, , Taichung Veterans General Hospital, ; Taichung, Taiwan
                [4 ]Division of Nephrology, Department of Internal Medicine, Lin Shin Hospital, No.36, Sec. 3, Hueijhong Rd., Nantun District, Taichung City, 40867 Taiwan
                Article
                Publisher ID: 1672
                DOI: 10.1186/s12882-019-1672-8
                PMC ID: 6945538
                PubMed ID: 31906890
                SO-VID: 6ef1d7d2-5669-47ef-bef4-86f969a3d020
                Copyright © © The Author(s). 2020
                License:

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                Date received : 8 August 2019
                Date accepted : 25 December 2019
                Categories
                Subject: Research Article
                Custom metadata
                issue-copyright-statement © The Author(s) 2020

                ScienceOpen disciplines: Nephrology
                Keywords: chronic active antibody mediated rejection,kidney transplantation,graft survival,adverse events
                Data availability:
                ScienceOpen disciplines: Nephrology
                Keywords: chronic active antibody mediated rejection, kidney transplantation, graft survival, adverse events

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